Despite intensive effort to discover drugs of value in the systemic treatment of human immunodeficiency virus (HIV) infections, such infections have been singularly resistant to chemotherapy. The intracellular and intimate relation to nuclear metabolism of virus reproduction makes it difficult to destroy a virus without irreparable damage to the host cell.
The discovery of the antiviral activity of vidarabine (9-.beta.-D-arabinofuranosyladenine monohydrate) has led to the preparation of a large number of synthetic nucleosides. To date, only one synthetic nucleoside, 3'-azido-3'-deoxythymidine (AZT) has been approved for treating certain AIDS patients, but it is a pallative, not a cure. ##STR2##
Although AZT is specifically active against retroviruses, its use has led to side effects, including anemia, headache, confusion, anxiety, nausea and insomnia. The AZT analog, 3'-azido-2',3'-dideoxyuridine ("AzddUrd" or "CS-87") has also been found to possess significant activity against HIV in vitro, and is currently in clinical trials to assess its efficacy in the treatment of AIDS. Ribavirin (RIB) has been used to treat viral respiratory infections caused by Rous Sarcoma Virus (RSV) in children. In early clinical trials, it inhibited viral replication and improved immune function in AIDS patients. Long-term studies in patients with AIDS-related complex (ARC) are in progress. ##STR3## The synthesis of adenine ("6-amino-purine") nucleoside analogues in which the pentose sugar has been replaced with tris(hydroxy)-substituted cyclopentyl residues has yielded compounds with substantial cytotoxic and antiviral activity. For example, the carbocyclic analogue of vidarabine, cyclaradine (Cy), is highly active against Herpes Simplex Virus Type 2 (HSV-2), but exhibits a low therapeutic index (TI.sub.50 =10) against HIV in vitro. ##STR4## T. L. Nagabhushan et al. (U.S. Pat. No. 4,636,383) disclose that a combination of cyclaradine and alpha-interferon exhibits a synergistic increase in potency against HSV-2 infections.
2',3'-Dideoxyinosine ("ddI") has also been shown to possess significant antiviral activity against HIV in vitro.
Vince et al. (U.S. patent application Ser. No. 07/146,262, filed Jan. 20, 1988) disclosed a new class of antiviral and antitumor compounds of general formula: (I). ##STR5## wherein Z is H, OH or NH.sub.2, Y is CH or N, the bond indicated by C.sub.1 '- - - C.sub.2 ' is absent or, in combination with the C.sub.1 '-C.sub.2 ' bond, is the unit CH.dbd.CH and X is selected from the group consisting of H, N(R).sub.2, SR, OR or halogen, wherein R is H, lower (C.sub.1 -C.sub.4)alkyl, aryl or mixtures thereof, and the pharmaceutically-acceptable salts thereof.
Although generally, when used alone, compounds of formula I are not active against Herpes Simplex Virus Type 2 (HSV-2), some of them exhibit specific antiviral activity against other viruses such as HSV-1, human cytomegalovirus (HCMV) and/or retroviruses such as HIV. Specifically, the compound of formula I, wherein X is OH, Z is NH.sub.2, Y is CH and the bond--is present, (14a) strongly inhibits HIV infectivity in vitro. However, the carbocyclic analogue of AZT is inactive against HIV, and it is clear that the structure-activity relationships between the variously substituted carbocyclic nucleosides which have been prepared and tested remain ill-defined.
Thus, a substantial need exists for chemotherapeutic agents effective to protect mammalian cells against infection by viruses such as HSV-2, HIV, EBV, varicellazoster vaccinia, human cytomegalovirus (HCMV) and the like.